PPARgamma - LIVING UP TO EXPECTATIONS?
It is less than a decade since the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARg) was first cloned, yet it has become one of the most extensively studied family members, implicated in a wide array of physiological and pathological processes ranging from adipocyte differentiation to lipid trafficking in macrophages and thyroid neoplasia. This receptor is therefore considered a key target for therapeutic modulation, as exemplified by the novel antidiabetic thiazolidinediones (TZDs), which are high affinity PPARg ligands.
Human genetic studies of polymorphisms/mutations within the receptor have yielded important insights into its key biological roles, especially in mediating insulin sensitivity. A relatively common polymorphism (Pro12Ala) within PPARg2 has been suggested to protect against the risk of developing type 2 diabetes; in contrast, we have described individuals harbouring severe loss-of-function dominant negative mutations in human PPARg (P467L, V290M), who exhibit severe insulin resistance, early onset diabetes and hypertension, together with partial lipodystrophy.
The mechanism by which PPARg activation regulates insulin sensitivity is poorly understood. Recent advances include the identification of adipocyte-derived mediators (resistin, adiponectin) or target genes (CAP) regulated by PPARg, which influence insulin action in skeletal muscle. In this context, we have described a digenic basis for insulin resistance with mutations in PPARG and an unrelated gene, PPP1R3, further supporting the contention that a 'metabolic dialogue' exists between skeletal muscle and adipose tissue.
Studies in monocytes/macrophages have shown that PPARg activation predominantly favours lipid efflux via the ABCA1 transporter, providing possible reassurance that TZD treatment is unlikely to promote foam cell formation or atherosclerosis.
Future goals include the development of mixed PPAR agonists or selective PPARg modulators which retain beneficial glucose-lowering or hypolipidaemic properties, but which lack the adverse effects (adipogenic, fluid retention) of current receptor activators.